This Grant is one of three, submitted in response to an RFA for an interdisciplinary approach to breast cancer. The overall aims of our three Grants are: (i) to develop novel methods for identifying and cloning genes that are differentially expressed in cancer vs. normal cells, positively as for oncogenes or negatively as for tumor suppressor genes; (ii) to investigate properties of these genes, and to select a subset useful for diagnosis, prognosis and therapy; (iii) to apply these findings to clinical samples. The approaches include cell biology and molecular genetics, and bridge the basic science-- clinical interface. Collaborations have been arranged in later years with Dr. Lloyd Old on applications of immunology, with Dr. Alan Sartorelli on pharmacology, and with Dr. Paul Zamecnik on antisense constructs. From what is already known, a large number of genes involved in the regulation of diseases, proliferation, aging, differentiation, DNA repair, chromosome function and cell-cell interaction will be shown to have suppressor or activator functions. These will provide important pieces of the cancer puzzle. Their identification will allow many researchers to integrate their studies into the entire picture. However, as yet only a small fraction of such genes have been identified (1), in part owing to the difficulty of methods for their selection. This Grant application is based upon the powerful Differential Display technique developed by Dr. Pardee, which provides a novel approach to this problem of gene selection. We propose to improve it in several important ways. In our collaborative effort with Drs. Sager, Smith and Thor, a selected subset of these genes will be cloned, sequenced and compared with data banks. We will prepare immunological (with Dr. Lloyd Old) and hybridization probes for diagnosis/prognosis, and their functions investigated for designing therapies including antisense constructs (with Dr. Paul Zamecnik) and drugs (with Dr. Alan Sartorelli) for treatment of breast cancers and other solid tumors. I will apply our results to develop methods for finding rare metastatic cells in early breast cancer patients.